Tumor Pro-Senescence Strategy to Enhance Mild Photothermal Therapy of Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) presents a substantial clinical challenge due to its aggressive nature and resistance to conventional therapies, thereby developing novel treatment strategies is critical. In this work, we take advantage of the insensitivity of heat shock protein (HSP) expression in senescent tumor cells to combine mild photothermal therapy (MPTT) for efficient DLBCL treatment. Insensitivity to HSPs implies that cells are less capable of activating their usual stress protection mechanisms during MPTT, which reduces their tolerance to heat damage. Consequently, the treatment can more effectively destroy target cells at lower temperatures while minimizing the risk of thermal injury to surrounding healthy tissues. Abemaciclib can inhibit CDK4/6 activity, thereby inhibiting Rb phosphorylation to suppress the activity of the E2F transcription factor and prevent the transition from G1 to S phase, leading to cell cycle arrest and ultimately cellular senescence. The experimental results indicated that abemaciclib effectively promoted the senescence of DLBCL cells, accompanied by a significant reduction in HSP70 expression. Subsequently, a novel near-infrared (NIR) absorbing organic polymer photothermal agent (PYIT-OD) with excellent optical properties and photostability was used for MPTT. The integration of pro-senescence strategies with MPTT, as evidenced by both in vitro and in vivo experimental outcomes, markedly enhanced treatment efficacy, effectively reducing damage to normal tissues at mild temperatures and enhancing antitumor effects. This work not only reveals potential biological mechanisms but also provides theoretical foundations and practical guidance for developing more precise and less toxic DLBCL treatment regimens in clinical practice.